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1.
Bioorg Med Chem ; 82: 117217, 2023 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-36889150

RESUMO

Complex natural products that bind to tubulin/microtubules come under the broad category of microtubule binding agents. The design of simplified analogs of previously reported bicyclic, microtubule depolymerizer, pyrrolo[2,3-d]pyrimidine, provided valuable structure-activity relationship data and led to the identification of novel monocyclic pyrimidine analogs of which 12 was 47-fold more potent (EC50 123 nM) for cellular microtubule depolymerization activity and 7.5-fold more potent (IC50 24.4 nM) at inhibiting the growth of MDA-MB-435 cancer cells, suggesting significantly better binding of the target within the colchicine site of tubulin compared to lead compound 1. This compound and others of this series of monocyclic pyrimidine analogs were able to overcome multidrug resistance due to the expression of the ßIII-isotype of tubulin and P-glycoprotein. In vivo evaluation of the most potent analog 12 in an MDA-MB-435 xenograft mouse model indicated, along with paclitaxel, that both compounds showed a trend towards lower tumor volume however neither compound showed significant antitumor activity in the trial. To our knowledge these are the first examples of simple substituted monocyclic pyrimidines as colchicine site binding antitubulin compounds with potent antitumor activity.


Assuntos
Antineoplásicos , Colchicina , Humanos , Camundongos , Animais , Colchicina/farmacologia , Colchicina/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/química , Microtúbulos/metabolismo , Relação Estrutura-Atividade , Pirimidinas/química , Antineoplásicos/química , Linhagem Celular Tumoral , Sítios de Ligação , Proliferação de Células
2.
FASEB J ; 37(4): e22846, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36856983

RESUMO

Colchicine is a broad-acting anti-inflammatory agent that has attracted interest for repurposing in atherosclerotic cardiovascular disease. Here, we studied its ability at a human equivalent dose of 0.5 mg/day to modify plaque formation and composition in murine atherosclerosis and investigated its actions on macrophage responses to atherogenic stimuli in vitro. In atherosclerosis induced by high-cholesterol diet, Apoe-/- mice treated with colchicine had 50% reduction in aortic oil Red O+ plaque area compared to saline control (p = .001) and lower oil Red O+ staining of aortic sinus lesions (p = .03). In vitro, addition of 10 nM colchicine inhibited foam cell formation from murine and human macrophages after treatment with oxidized LDL (ox-LDL). Mechanistically, colchicine downregulated glycosylation and surface expression of the ox-LDL uptake receptor, CD36, and reduced CD36+ staining in aortic sinus plaques. It also decreased macrophage uptake of cholesterol crystals, resulting in lower intracellular lysosomal activity, inhibition of the NLRP3 inflammasome, and reduced secretion of IL-1ß and IL-18. Colchicine's anti-atherosclerotic actions were accentuated in a mouse model of unstable plaque induced by carotid artery tandem stenosis surgery, where it decreased lesion size by 48% (p = .01), reduced lipid (p = .006) and necrotic core area (p = .007), increased collagen content and cap-to-necrotic core ratio (p = .05), and attenuated plaque neutrophil extracellular traps (p < .001). At low dose, colchicine's effects were not accompanied by the evidence of microtubule depolymerization. Together, these results show that colchicine exerts anti-atherosclerotic and plaque-stabilizing effects at low dose by inhibiting foam cell formation and cholesterol crystal-induced inflammation. This provides a new framework to support its repurposing for atherosclerotic cardiovascular disease.


Assuntos
Aterosclerose , Doenças Cardiovasculares , Estenose das Carótidas , Humanos , Animais , Camundongos , Células Espumosas , Colchicina , Colesterol
3.
Sci Rep ; 13(1): 4854, 2023 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-36964265

RESUMO

Gloriosine, the predominant metabolite of Gloriosa superba L., shares chemical properties with colchicine. We analyze the microtubule-binding affinity of gloriosine at the colchicine binding site (CBS) using an in silico-in vivo approach. The In silico docking of gloriosine showed a binding score of (-) 7.5 kcal/Mol towards ß-tubulin at CBS and was validated by overlapping the coupling pose of the docked ligand with co-crystallized colchicine. 2D plots (Ligplot +) showed > 85% overlap between gloriosine and colchicine. The ADMET profile of gloriosine was in accordance with Lipinski's rule of five. Gloriosine belongs to class II toxicity with anLD50 value of 6 mg/kg. In vivo and transmission electron microscopy studies revealed that gloriosine induces abnormalities in cell division such as condensed chromosomes in C-metaphase and enlarged nucleus with increased nuclear material. Gloriosine treated cells exhibited mitotic index of about 14% compared to control of 24% and high anti-proliferative activity i.e. 63.94% cell viability at a low concentration (0.0004 mg/ml). We conclude that gloriosine has a strong affinity for ß-tubulin at CBS and thus can be used as a colchicine alternative in cytology and other clinical conditions.


Assuntos
Colchicina , Tubulina (Proteína) , Colchicina/química , Tubulina (Proteína)/metabolismo , Microtúbulos/metabolismo , Sítios de Ligação , Ligação Proteica
4.
J Pharm Biomed Anal ; 228: 115317, 2023 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-36868026

RESUMO

As an effective treatment for acute gouty arthritis and cardiovascular disease, colchicine is also a toxic alkaloid and may cause poisoning or even death in overdose. The study of colchicine elimination and the diagnosis of poisoning etiology need the rapid and accurate quantitative analysis method in biological matrix. An analytical method was developed for colchicine in plasma and urine by in-syringe dispersive solid phase extraction (DSPE) followed by liquid chromatography-triple quadrupole mass spectrometry (LC-MS/MS). Sample extraction and protein precipitation were proceeded with acetonitrile. The extract was cleaned by in-syringe DSPE. An XBridge™ BEH C18 column(100 mm × 2.1 mm, 2.5 µm)was used to separate colchicine by gradient elution with mobile phase of 0.01% (v/v) ammonia-methanol. The amount and filling sequence of magnesium sulfate (MgSO4) and primary secondary amine (PSA) suitable for in-syringe DSPE were studied. Scopolamine was screened as the quantitative internal standard (IS) for colchicine analysis according to the consistency of recovery rate, chromatographic retention time and matrix effects. The limits of detection for colchicine in plasma and urine were both 0.06 ng mL-1 and the limits of quantitation were both 0.2 ng mL-1. The linear range was 0.04 - 20 ng mL-1 (Equivalent to 0.2-100 ng mL-1 in plasma or urine) with a correlation coefficient r > 0.999. By IS calibration, the average recoveries at three spiking levels in plasma and urine were 95.3-102.68% and 93.9-94.8% with the relative standard deviations (RSDs) of 2.9-5.7% and 2.3-3.4%, respectively. The matrix effects, stability, dilution effects and carryover for determination of colchicine in plasma and urine were also evaluated. The elimination of colchicine within 72-384 h post-ingestion was studied for a poisoning patient with the doses of 1 mg d-1 for 39 days and then 3 mg d-1 for 15 days).


Assuntos
Colchicina , Espectrometria de Massas em Tandem , Humanos , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Seringas , Extração em Fase Sólida , Cromatografia Líquida de Alta Pressão/métodos
5.
Molecules ; 28(6)2023 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-36985431

RESUMO

Bioassay-guided isolation from Camellia sinensis (Theaceae) and Colchicum luteum (Liliaceae) utilizing an in vitro model of protease assay revealed colchicine (1) and caffeine (2) from chloroform fractions, respectively. Their structures were validated using spectral techniques. The purified compounds were further optimized with Gaussian software utilizing the B3LYP functional and 6-31G(d,p) basis set. The result files were utilized to determine several global reactivity characteristics to explain the diverse behavior of the compounds. Colchicine (1) showed a higher inhibition of protease activity (63.7 ± 0.5 %age with IC50 = 0.83 ± 0.07 mM), compared with caffeine (2) (39.2 ± 1.3 %age). In order to determine the type of inhibition, compound 1 was further studied, and, based on Lineweaver-Burk/Dixon plots and their secondary replots, it was depicted that compound 1 was a non-competitive inhibitor of this enzyme, with a Ki value of 0.690 ± 0.09 mM. To elucidate the theoretical features of protease inhibition, molecular docking studies were performed against serine protease (PDB #1S0Q), which demonstrated that compound 1 had a strong interaction with the different amino acid residues located on the active site of this understudied enzyme, with a high docking score of 16.2 kcal/mol.


Assuntos
Alcaloides , Camellia sinensis , Colchicum , Simulação de Acoplamento Molecular , Colchicum/química , Camellia sinensis/química , Peptídeo Hidrolases , Cafeína , Alcaloides/farmacologia , Endopeptidases , Colchicina , Bioensaio
6.
J Dtsch Dermatol Ges ; 21(3): 239-243, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36892188

RESUMO

Colchicine, which was already used by the ancient Egyptians, has recently experienced a renaissance in various medical disciplines, including dermatology. However, due to the potentially significant side effects of systemic use, many clinicians are cautious in their use of colchicine. This review provides a practical overview of the data on the established and emerging use of systemic and topical colchicine in dermatologic diseases.


Assuntos
Colchicina , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Colchicina/uso terapêutico , Colchicina/farmacologia
9.
J Med Chem ; 66(5): 3588-3620, 2023 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-36802449

RESUMO

Herein, a series of quinazoline and heterocyclic fused pyrimidine analogues were designed and synthesized based on the X-ray co-crystal structure of lead compound 3a, showing efficacious antitumor activities. Two analogues, 15 and 27a, exhibited favorable antiproliferative activities, which were more potent than lead compound 3a by 10-fold in MCF-7 cells. In addition, 15 and 27a exhibited potent antitumor efficacy and tubulin polymerization inhibition in vitro. 15 reduced the average tumor volume by 80.30% (2 mg/kg) in the MCF-7 xenograft model and 75.36% (4 mg/kg) in the A2780/T xenograft model, respectively. Most importantly, supported by structural optimization and Mulliken charge calculation, X-ray co-crystal structures of compounds 15, 27a, and 27b in complex with tubulin were resolved. In summary, our research provided the rational design strategy of colchicine binding site inhibitors (CBSIs) based on X-ray crystallography with antiproliferation, antiangiogenesis, and anti-multidrug resistance properties.


Assuntos
Antineoplásicos , Neoplasias Ovarianas , Humanos , Feminino , Colchicina/metabolismo , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/farmacologia , Moduladores de Tubulina/uso terapêutico , Linhagem Celular Tumoral , Raios X , Desenho de Fármacos , Sítios de Ligação , Pirimidinas/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de Células , Relação Estrutura-Atividade
10.
Crit Care ; 27(1): 49, 2023 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-36747296

RESUMO

BACKGROUND: Recent high-quality trials have shown that the anti-inflammatory effects of colchicine reduce the risk of cardiovascular events in patients suffering post-myocardial infarction and chronic coronary disease. The effect of colchicine in patients undergoing non-coronary artery bypass grafting (non-CABG) with cardiopulmonary bypass remains unclear. We aim to evaluate the effect of colchicine on myocardial protection in patients who underwent non-CABG cardiac surgery. METHOD: Patients were randomly assigned to colchicine or placebo groups starting 72 h before scheduled cardiac surgery and for 5 days thereafter (0.5 mg daily).The primary outcome was the level of cardiac troponin T (cTnT) at postoperative 48 h. The secondary outcomes included troponin I (cTnI) and creatine kinase-MB (CK-MB), inflammatory biomarkers (procalcitonin and interleukin-6, etc.), and adverse events (30-day mortality, stroke, ECMO and IABP use, etc.). RESULTS: A total of 132 patients underwent non-CAGB cardiac surgery, 11were excluded because of diarrhea (n = 6) and long aortic cross-clamp time > 2 h (n = 5), 59 were assigned to the colchicine group and 62 to the placebo group. Compared with the placebo group, cTnT (median: 0.3 µg/L, IQR 0.2-0.4 µg/L vs. median: 0.4 µg/L, IQR 0.3-0.6 µg/L, P < 0.01), cardiac troponin I (median: 0.9 ng/ml, IQR 0.4-1.7 ng/ml vs. median: 1.3 ng/ml, IQR 0.6-2.3 ng/ml, P = 0.02), CK-MB (median: 1.9 ng/ml, IQR 0.7-3.2 ng/ml vs. median: 4.4 ng/ml, IQR 1.5-8.2 ng/ml, P < 0.01), and interleukin-6 (median: 73.5 pg/ml, IQR 49.6-125.8 pg/ml vs. median: 101 pg/ml, IQR 57.5-164.7 pg/ml, P = 0.048) were significantly reduced in colchicine group at postoperative 48 h. For safety evaluation, the colchicine (n = 65) significantly decreased post-pericardiotomy syndrome (3.08% vs. 17.7%, P < 0.01) and increased the rate of diarrhea (9.23% vs. 0, P = 0.01) compared with the placebo group (n = 62). No significant difference was observed in other adverse events between the two groups. CONCLUSION: A short perioperative course of low-dose colchicine was effective to attenuate the postoperative biomarkers of myocardial injury and inflammation, and to decrease the postoperative syndrome compared with the placebo. Trial registration ChiCTR2000040129. Registered 22nd Nov. 2020. This trial was registered before the first participant was enrolled. http://www.chictr.org.cn/showproj.aspx?proj=64370 .


Assuntos
Infarto do Miocárdio , Troponina I , Humanos , Colchicina/farmacologia , Colchicina/uso terapêutico , Interleucina-6 , Creatina Quinase Forma MB , Troponina T , Biomarcadores
11.
Bioorg Med Chem Lett ; 83: 129166, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36736495

RESUMO

Tubulin, a potential target for antitumor drug discovery, contains three main binding sites for clinical inhibitors: colchicine, vinblastine, and paclitaxel. CA-4 has been reported to be a classic tubulin inhibitor targeting the colchicine site. Herein, based on the structural modification of CA-4, 48 novel compounds were designed and synthesized by selecting structural fragments with various biological activities to replace the cis double bond of CA-4. Among these compounds, compound 8p was the most effective tubulin inhibitor (IC50 = 65 nM aganist HepG2 cells). Immunofluorescence experiment confirmed the anti-tumor effect of 8p by destroying the network structure of microtubules. Further studies showed that 8p induced tumor cell apoptosis, arrested cell cycle, inhibited tumor cell migration and invasion.


Assuntos
Antineoplásicos , Moduladores de Tubulina , Moduladores de Tubulina/química , Colchicina/química , Linhagem Celular Tumoral , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Antineoplásicos/química , Tubulina (Proteína)/metabolismo , Sítios de Ligação , Relação Estrutura-Atividade
12.
Future Med Chem ; 15(1): 73-95, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36756851

RESUMO

Microtubules, formed by α- and ß-tubulin heterodimer, are considered as a major target to prevent the proliferation of tumor cells. Microtubule-targeted agents have become increasingly effective anticancer drugs. However, due to the relatively sophisticated chemical structure of taxane and vinblastine, their application has faced numerous obstacles. Conversely, the structure of colchicine binding site inhibitors (CBSIs) is much easier to be modified. Moreover, CBSIs have strong antiproliferative effect on multidrug-resistant tumor cells and have become the mainstream research orientation of microtubule-targeted agents. This review focuses mainly on the recent advances of CBSIs during 2017-2022, attempts to depict their biological activities to analyze the structure-activity relationships and offers new perspectives for designing next generation of novel CBSIs.


Assuntos
Antineoplásicos , Moduladores de Tubulina , Moduladores de Tubulina/farmacologia , Moduladores de Tubulina/química , Colchicina/metabolismo , Tubulina (Proteína)/metabolismo , Ligação Proteica , Sítios de Ligação , Antineoplásicos/farmacologia , Antineoplásicos/química , Relação Estrutura-Atividade , Proliferação de Células , Linhagem Celular Tumoral
13.
Ann Intern Med ; 176(2): JC17, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36745891

RESUMO

SOURCE CITATION: Eikelboom JW, Jolly SS, Belley-Cote EP, et al. Colchicine and aspirin in community patients with COVID-19 (ACT): an open-label, factorial, randomised, controlled trial. Lancet Respir Med. 2022;10:1160-8. 36228639.


Assuntos
Aspirina , COVID-19 , Humanos , Aspirina/uso terapêutico , Colchicina/uso terapêutico , Progressão da Doença , Pacientes Ambulatoriais , Resultado do Tratamento
14.
Int J Mol Sci ; 24(3)2023 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-36768804

RESUMO

Several lines of evidence have clearly indicated that inflammation plays a pivotal role in the development of atherosclerosis and of its thrombotic complications such as acute coronary syndromes or ischemic stroke. Thus, it has been postulated that the use of anti-inflammatory agents might be extremely useful to improve cardiovascular outcome. Recently, increasing attention has been reserved to one of the oldest plant-derived drugs still in use in clinical practice, colchicine that has been used as drug to treat inflammatory diseases such gout or Mediterranean fever. To date, current guidelines of the European Society of Cardiology have included colchicine as first line choice for treatment of acute and recurrent pericarditis. Moreover, several studies have investigated its role in the clinical scenarios of cardiovascular disease including chronic and acute coronary syndromes with promising results. In this review, starting from a description of the mechanism(s) involved behind its anti-inflammatory effects, we give an overview on its potential effects in atherothrombosis and finally present an updated overview of clinical evidence on the role of this drug in cardiovascular disease.


Assuntos
Síndrome Coronariana Aguda , Pericardite , Trombose , Humanos , Colchicina/uso terapêutico , Síndrome Coronariana Aguda/tratamento farmacológico , Inflamação/tratamento farmacológico , Pericardite/tratamento farmacológico , Trombose/tratamento farmacológico
15.
BMJ Open ; 13(2): e067910, 2023 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-36828654

RESUMO

OBJECTIVE: To evaluate the effect of colchicine and high-intensity rosuvastatin in addition to standard of care on the progression of COVID-19 disease in hospitalised patients. DESIGN: A pragmatic, open-label, multicentre, randomised controlled trial conducted from October 2020 to September 2021. Follow-up was conducted at 30 and 60 days. The electronic medical record was used at all stages of the trial including screening, enrolment, randomisation, event ascertainment and follow-up. SETTING: Four centres in the Yale New Haven Health System. PARTICIPANTS: Non-critically ill hospitalised patients with COVID-19. INTERVENTIONS: Patients were randomised 1:1 to either colchicine plus high-intensity rosuvastatin in addition to standard of care versus standard of care alone. Assigned treatment was continued for the duration of index hospitalisation or 30 days, whichever was shorter. PRIMARY AND SECONDARY OUTCOME MEASURES: The prespecified primary endpoint was progression to severe COVID-19 disease (new high-flow or non-invasive ventilation, mechanical ventilation, need for vasopressors, renal replacement therapy or extracorporeal membrane oxygenation, or death) or arterial/venous thromboembolic events (ischaemic stroke, myocardial infarction, deep venous thrombosis or pulmonary embolism) evaluated at 30 days. RESULTS: Among the 250 patients randomised in this trial (125 to each arm), the median age was 61 years, 44% were women, 15% were Black and 26% were Hispanic/Latino. As part of the standard of care, patients received remdesivir (87%), dexamethasone (92%), tocilizumab (18%), baricitinib (2%), prophylactic/therapeutic anticoagulation (98%) and aspirin (91%). The trial was terminated early by the data and safety monitoring board for futility. No patients were lost to follow-up due to electronic medical record follow-up. There was no significant difference in the primary endpoint at 30 days between the active arm and standard of care arm (15.2% vs 8.8%, respectively, p=0.17). CONCLUSIONS: In this small, open-label, randomised trial of non-critically ill hospitalised patients with COVID-19, the combination of colchicine and rosuvastatin in addition to standard of care did not appear to reduce the risk of progression of COVID-19 disease or thromboembolic events, although the trial was underpowered due to a lower-than-expected event rate. The trial leveraged the power of electronic medical records for efficiency and improved follow-up and demonstrates the utility of incorporating electronic medical records into future trials. TRIAL REGISTRATION: NCT04472611.


Assuntos
Isquemia Encefálica , COVID-19 , Acidente Vascular Cerebral , Feminino , Humanos , Pessoa de Meia-Idade , Masculino , Rosuvastatina Cálcica , SARS-CoV-2 , Colchicina , Resultado do Tratamento
16.
J Investig Med ; 71(2): 124-131, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: covidwho-2195109

RESUMO

This study was designed to evaluate the effects of colchicine in the improvement of clinical outcomes of hospitalized COVID-19 patients. This prospective, randomized, double-blind, placebo-controlled clinical trial was conducted on adult patients (>18 years) with severe COVID-19. The included patients were randomly (1:1) assigned to the colchicine (2 mg loading dose followed by 0.5 mg twice daily for 7 days) or placebo group. Both groups received remdesivir and interferon beta-1b. The primary outcome of the study was to receive clinical response as ordinal scale of 1 or 2. Secondary outcomes were hospital complications and 28-day mortality. Between February and May 2021, 110 patients were included and 106 of them were analyzed. Baseline clinical characteristics and demographics were not significantly different. According to the ordinal scale, 30 patients in the control group (58.8%) responded to treatment within 7 days, while 35 patients (63.6%) in the colchicine group showed the same response (p = 0.61, odds ratio (OR) = 1.23, 95% CI [0.560-2.68]). On the 14th day, 87.3% of the colchicine group (n = 48) and 82.4% of the control group (n = 42) responded (p = 0.48, OR = 1.47, 95% CI [0.50.3-4.29]. In addition, 28-day mortality, intensive care unit admission, and hospital duration were not different between the groups (p = 0.99, 0.59, 0.06). Diarrhea and nausea were the major side effects dominant in the colchicine group. Colchicine showed no beneficial effects on clinical improvement and hospital complications in patients with COVID-19. Moreover, in case of prescription, the safety concerns of colchicine, specially gastrointestinal side effects, should be taken into account.


Assuntos
COVID-19 , Adulto , Humanos , Colchicina/uso terapêutico , SARS-CoV-2 , Estudos Prospectivos , Hospitalização , Método Duplo-Cego , Resultado do Tratamento
17.
Eur J Med Res ; 28(1): 10, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36609359

RESUMO

BACKGROUND: Gouty arthritis (GA) is a chronic systemic disease with recurrent acute monoarthritis. In a previous study, a higher incidence of acute flares was observed during the initial marked decrease in serum urate level. Our study evaluated the effect of early urate-lowering therapy in patients with acute GA flares. METHODS: This study included 40 patients with acute GA; of them, 20 received colchicine 0.5 mg colchicine twice daily, while 20 received probenecid 500 mg and colchicine 0.5 mg twice daily. We evaluated GA severity and laboratory data for 2 weeks after the initial therapy. Medians and interquartile ranges (IQRs) were calculated to evaluate clinical presentations between these two groups. RESULTS: Rapidly decreasing median serum uric acid levels was found in the patients treated with probenecid and colchicine compared with the patients treated with colchicine alone on day 8 (- 1.9 [IQR, - 3.7 to 0] vs 0.8 [IQR, - 0.1-2.2]; P < 0.001). However, the median decrease in visual analog scale score did not differ significantly between the two groups (- 5.5 [IQR, - 8.0 to - 3.0] vs - 3.5 [IQR, - 5.9 to - 2.0]; P = 0.080). CONCLUSION: No significant increase was noted in acute gout flare severity or duration among GA patients treated with early aggressive control of hyperuricemia using probenecid plus colchicine.


Assuntos
Artrite Gotosa , Gota , Humanos , Artrite Gotosa/tratamento farmacológico , Artrite Gotosa/induzido quimicamente , Supressores da Gota/uso terapêutico , Supressores da Gota/efeitos adversos , Ácido Úrico , Probenecid/uso terapêutico , Exacerbação dos Sintomas , Colchicina/uso terapêutico , Colchicina/efeitos adversos , Doença Crônica
18.
J Mol Model ; 29(2): 36, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36627468

RESUMO

CONTEXT: Phytocompounds xanthatin and 8-epi-xanthatin, obtained from Xanthium chinese Mill, showed antitumoral activity in vitro related to the microtubules destabilizing properties of these phytocompounds. Five binding sites for microtubule destabilizing agents have been characterized on tubulin by high-resolution X-ray crystallography: vinca domain, colchicine, pironetin, maytansine site, and more recently, the seventh site. This work aims to develop a comprehensive computational strategy to understand and eventually predict the interaction between xanthatin and 8-epi-xanthatin with the destabilizing-antimitotic binding domain of the tubulin heterodimer. In addition, we propose a putative binding site for these phytocompounds into the microtubule destabilizing binding sites on the tubulin heterodimer. Xanthanolides showed higher stability in the colchicine and pironetin binding sites, whit a greater affinity for the former. In addition, we found that xanthanolides and non-classical colchicine binding site inhibitors share a high structural similarity. METHODS: The 3D structures for xanthatin and 8-epi-xanthatin were obtained using DFT with the hybrid functional B3LYP and the base 6-31G (d,p), implemented in Gaussian 09. The 3D coordinates for tubulin proteins were downloaded from PDB. The complexes tubulin-xanthanolides were predicted using a Monte-Carlo iterated search combined with the BFGS gradient-based optimizer implemented in the AutoDock Vina. The xanthanolides-tubulin complexes were energy minimized by molecular dynamics simulations at vacuum, and their stabilities were evaluated by solvated molecular dynamics simulations during 100 ns. All molecular dynamics simulations were performed using the conjugate gradient method implemented in NAMD2 and CHARMM36 forcefield.


Assuntos
Antineoplásicos , Colchicina , Colchicina/farmacologia , Colchicina/química , Tubulina (Proteína)/metabolismo , Furanos/farmacologia , Sítios de Ligação , Microtúbulos , Antineoplásicos/farmacologia
19.
Pediatr Rheumatol Online J ; 21(1): 4, 2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36624531

RESUMO

INTRODUCTION: Familial Mediterranean Fever (FMF) is the most common monogentic autoinflammatory disease. FMF results from mutations in MEFV, which lead to a pro-inflammatory state and increased production of Interleukin 1 beta subunit (IL-1b) by myeloid cells. Despite the overall positive results obtained with anti-IL-1 agents in FMF patients, little is known about the long-term growth impact of these drugs in the pediatric population. OBJECTIVES: To assess the long-term body weight and height trajectories in children with FMF treated with anti-IL-1 agents. METHODS: We conducted a retrospective analysis of 646 pediatric FMF patients followed in our center, of whom 22 were treated with either anakinra (36.3%) and/or canakinumab (90.9%). Patients were assessed for demographic, clinical and genetic characteristics and were followed for a mean of 3.05 ± 1.75 years. Data of height and weight percentiles were recorded before and after treatment. RESULTS: The most common indication for IL-1 blockers treatment was colchicine resistance (66.6%). Ninety percent of those patients had a moderate or severe disease according to the Pras score and had higher proportion of M694V homozygosity compared with patients who did not require anti IL-1 agents (95.2% vs. 30.5%, p < 0.001). Overall, anakinra and canakinumab resulted in a complete response in 80% of patients and exhibited low rates of adverse effects. We found a significant increase in height and body weight percentiles following treatment (19.6 ± 16% vs. 30.8 ± 23%, p = 0.007, and 29.5 ± 30% vs. 39.1 ± 36%, p = 0.043, respectively). CONCLUSION: Treatment with anti-IL-1 agents in children with FMF is effective and safe and may potentiate long-term growth.


Assuntos
Colchicina , Febre Familiar do Mediterrâneo , Criança , Humanos , Colchicina/uso terapêutico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre Familiar do Mediterrâneo/genética , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Estudos Retrospectivos , Peso Corporal , Pirina
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